Abstract: HIV has claimed >25 million lives. Two decades of research, but no vaccine. Theoretically, generation of CD8 T cell immunity may succeed where traditional, neutralizing antibody-dependent, vaccines have failed. But, nascent efforts have consistently failed to prevent chronic SIV infection in monkeys following a stringent challenge, and the first human HIV CD8 T cell vaccine trial was a complete failure. Why? Is a preventative CD8 T cell vaccine impossible, as many now suggest? We hypothesize that past efforts have been crippled by a safety-first approach and relative ignorance of the importance of memory CD8 T cell quantity, quality, and location to protection. Current approaches are largely refinements of past failures. A bolder approach is long overdue, at least in animal models where safety requirements are less stringent. What could SIV specific memory CD8 T cells accomplish if they were 500-fold more plentiful than what is established by current vaccination strategies? What if these cells were preferentially located at common portals of viral entry and destroyed infected host tissue quickly upon contact? If a vaccine converted most CD8 T cells into HIV or SIV specific memory cells, could they fully protect the host and eliminate the infection completely? Or are CD8 T cells incapable of fulfilling this goal, even under ideal scenarios? This proposal will answer these essential questions. Moreover, it will test the limits of memory CD8 T cell generation, and define CD8 T cell correlates of protection. If successful, this study may demonstrate that a preventative HIV vaccine is theoretically possible. Public Health Relevance: This proposal will investigate how memory CD8 T cells are generated via vaccination, and determine the relationship between memory CD8 T cell quantity, quality, and location and their contribution to protection from infection. These findings will have direct relevance to vaccination and to establishing correlates of CD8 T cell dependent protective immunity.